title: ERCC1, MLH1, MSH2, MSH6, and βIII-tubulin: resistance proteins associated with response and outcome to platinum-based chemotherapy in malignant pleural mesothelioma.
abstract: BACKGROUND
  Platinum-based chemotherapy is besides the standard antifolate therapy with pemetrexed, the cornerstone for treatment of patients with malignant pleural mesothelioma (MPM), and its efficacy depends on several DNA repair enzymes. Therefore, these enzymes could be biomarkers for "tailoring" chemotherapy. This study evaluated enzymes involved in repair of platinum-caused DNA damage, potentially resulting in a biomarker panel associated with patient response and outcome to platinum-based chemotherapy.
  
  
  METHODS
  Pre- or posttreatment specimens from a total of 103 patients with MPM who were undergoing first-line chemotherapy were tested separately. Immunohistochemistry for ERCC1 (endonuclease excision repair cross-complementing 1), MLH1 (MutL homologue 1), MutS homologue (MSH) 2, MSH6, and βIII-tubulin protein expression, and pyrosequencing for ERCC1 codon 118 and C8092A polymorphisms were performed, and their results were correlated to clinicopathologic data.
  
  
  RESULTS
  ERCC1, MLH1, MSH2, MSH6, and βIII-tubulin were expressed in human MPM specimens at different intensities. When considering only pretreatment specimens, MSH6 protein levels were correlated to progression during chemotherapy (P = .0281). MLH1 protein levels (P = .0205), and ERCC1 codon 118 polymorphisms (P ≤ .0001) were significantly associated with progression-free survival. A significant association between ERCC1 protein levels and overall survival was noted (P = .032). Analyses of posttreatment specimens revealed significant associations between βIII-tubulin protein levels and progression-free survival (P = .0066). ERCC1 C8092A polymorphisms were significantly associated with progression-free survival and overall survival (P = .0463 and P = .0080, respectively) in this group.
  
  
  CONCLUSIONS
  Enzymes involved in DNA repair mechanisms are associated with patient response and outcome to platinum-based chemotherapy. Their assessment may be a helpful tool to tailor platinum-based chemotherapy of MPM patients who might expect the largest clinical benefit. Prospective validation of this biomarker panel is warranted.
authors.affiliation: Institute of Pathology and Neuropathology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany. saskia.ting@uk-essen.de
authors.forename: Saskia
authors.initials: S
authors.lastname: Ting
authors.forename: Fabian D
authors.initials: FD
authors.lastname: Mairinger
authors.forename: Thomas
authors.initials: T
authors.lastname: Hager
authors.forename: Stefan
authors.initials: S
authors.lastname: Welter
authors.forename: Wilfried E
authors.initials: WE
authors.lastname: Eberhardt
authors.forename: Jeremias
authors.initials: J
authors.lastname: Wohlschlaeger
authors.forename: Kurt W
authors.initials: KW
authors.lastname: Schmid
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Christoph
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D016190:Carboplatin / Q000008:administration & dosage; D002945:Cisplatin / Q000008:administration & dosage; D004268:DNA-Binding Proteins / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D004720:Endonucleases / Q000378:metabolism*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality*; D008297:Male; D008654:Mesothelioma / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality*; D000086002:Mesothelioma, Malignant; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000378:metabolism*; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000378:metabolism*; D011379:Prognosis; D015996:Survival Rate; D046888:Tissue Array Analysis; D014404:Tubulin / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C498585:TUBB3 protein, human; D014404:Tubulin; D016190:Carboplatin; C071447:ERCC1 protein, human; D004720:Endonucleases; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D002945:Cisplatin
keywords: Biomarker; DNA repair; Immunohistochemistry; Pyrosequencing; Tailored therapy